Interdomain stabilization impairs CD4 binding and improves immunogenicity of the HIV-1 envelope trimer
Peng Zhang
(1)
,
Jason Gorman
(2)
,
Hui Geng
(2)
,
Qingbo Liu
(1)
,
Yin Lin
(1)
,
Yaroslav Tsybovsky
(3)
,
Eden Go
(4)
,
Barna Dey
(5)
,
Tsion Andine
(1)
,
Alice Kwon
(1)
,
Mit Patel
(1)
,
Deepali Gururani
(1)
,
Ferzan Uddin
(1)
,
Christina Guzzo
(1)
,
Raffaello Cimbro
(1)
,
Huiyi Miao
(1)
,
Krisha Mckee
(2)
,
Gwo-Yu Chuang
(2)
,
Loïc M Martin
(6, 7, 8)
,
Francesca Sironi
(9)
,
Mauro S. Malnati
(9)
,
Heather Desaire
(4)
,
Edward A. Berger
(5)
,
John R. Mascola
(2)
,
Michael A. Dolan
(5)
,
Peter D. Kwong
(2)
,
Paolo Lusso
(1)
1
Laboratory of Immunoregulation [Bethesda, MD, USA]
2 VRC - Vaccine Research Center
3 FNLCR - Frederick National Laboratory for Cancer Research
4 KU - University of Kansas [Lawrence]
5 NIAID-NIH - National Institute of Allergy and Infectious Diseases [Bethesda]
6 JOLIOT - Institut des Sciences du Vivant Frédéric JOLIOT
7 SIMoS - Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO)
8 MTS - Médicaments et Technologies pour la Santé
9 San Raffaele Scientific Institute
2 VRC - Vaccine Research Center
3 FNLCR - Frederick National Laboratory for Cancer Research
4 KU - University of Kansas [Lawrence]
5 NIAID-NIH - National Institute of Allergy and Infectious Diseases [Bethesda]
6 JOLIOT - Institut des Sciences du Vivant Frédéric JOLIOT
7 SIMoS - Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO)
8 MTS - Médicaments et Technologies pour la Santé
9 San Raffaele Scientific Institute
Peng Zhang
- Fonction : Auteur
- PersonId : 762416
- ORCID : 0000-0002-6129-567X
Loïc M Martin
- Fonction : Auteur
- PersonId : 740796
- IdHAL : loic-mjc-martin
- ORCID : 0000-0002-7940-2955
- IdRef : 169807029
Résumé
The HIV-1 envelope (Env) spike is a trimer of gp120/gp41 heterodimers that mediates viral entry.
Binding to CD4 on the host cell membrane is the first essential step for infection but disrupts the
native antigenic state of Env, posing a key obstacle to vaccine development. We locked the HIV-1
Env trimer in a pre-fusion configuration, resulting in impaired CD4 binding and enhanced binding
to broadly neutralizing antibodies. This design was achieved via structure-guided introduction of
neo-disulfide bonds bridging the gp120 inner and outer domains and was successfully applied to
soluble trimers and native gp160 from different HIV-1 clades. Crystallization illustrated the
structural basis for CD4-binding impairment. Immunization of rabbits with locked trimers from
two different clades elicited neutralizing antibodies against tier-2 viruses with a repaired glycan
shield regardless of treatment with a functional CD4 mimic. Thus, interdomain stabilization
provides a widely applicable template for the design of Env-based HIV-1 vaccines.
Format du dépôt | Fichier |
---|---|
Type de dépôt | Article dans une revue |
Titre |
en
Interdomain stabilization impairs CD4 binding and improves immunogenicity of the HIV-1 envelope trimer
|
Résumé |
en
The HIV-1 envelope (Env) spike is a trimer of gp120/gp41 heterodimers that mediates viral entry.
Binding to CD4 on the host cell membrane is the first essential step for infection but disrupts the
native antigenic state of Env, posing a key obstacle to vaccine development. We locked the HIV-1
Env trimer in a pre-fusion configuration, resulting in impaired CD4 binding and enhanced binding
to broadly neutralizing antibodies. This design was achieved via structure-guided introduction of
neo-disulfide bonds bridging the gp120 inner and outer domains and was successfully applied to
soluble trimers and native gp160 from different HIV-1 clades. Crystallization illustrated the
structural basis for CD4-binding impairment. Immunization of rabbits with locked trimers from
two different clades elicited neutralizing antibodies against tier-2 viruses with a repaired glycan
shield regardless of treatment with a functional CD4 mimic. Thus, interdomain stabilization
provides a widely applicable template for the design of Env-based HIV-1 vaccines.
|
Auteur(s) |
Peng Zhang
1
, Jason Gorman
2
, Hui Geng
2
, Qingbo Liu
1
, Yin Lin
1
, Yaroslav Tsybovsky
3
, Eden Go
4
, Barna Dey
5
, Tsion Andine
1
, Alice Kwon
1
, Mit Patel
1
, Deepali Gururani
1
, Ferzan Uddin
1
, Christina Guzzo
1
, Raffaello Cimbro
1
, Huiyi Miao
1
, Krisha Mckee
2
, Gwo-Yu Chuang
2
, Loïc M Martin
6, 7, 8
, Francesca Sironi
9
, Mauro S. Malnati
9
, Heather Desaire
4
, Edward A. Berger
5
, John R. Mascola
2
, Michael A. Dolan
5
, Peter D. Kwong
2
, Paolo Lusso
1
1
Laboratory of Immunoregulation [Bethesda, MD, USA]
( 562573 )
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
- États-Unis
2
VRC -
Vaccine Research Center
( 90574 )
- National Institute of Allergy and Infectious Disease National Institutes of Health Bethesda, MD
- États-Unis
3
FNLCR -
Frederick National Laboratory for Cancer Research
( 362325 )
- 8560 Progress Drive, Frederick, Maryland
- États-Unis
4
KU -
University of Kansas [Lawrence]
( 87313 )
- 1450 Jayhawk Blvd, Lawrence, KS 66045
- États-Unis
5
NIAID-NIH -
National Institute of Allergy and Infectious Diseases [Bethesda]
( 103678 )
- 5601 Fishers Lane, Suite 6D, MSC 9804 - Bethesda, MD 20892-9804
- États-Unis
6
JOLIOT -
Institut des Sciences du Vivant Frédéric JOLIOT
( 487603 )
- DRF
CEA
Gif-sur-Yvette
- France
7
SIMoS -
Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO)
( 40493 )
- Service d'Ingénierie Moléculaire pour la Santé
(ex SIMOPRO Servce d'ingénierie moléculaire des protéines)
CEA Saclay 91191 Gif sur Yvette cedex
- France
8
MTS -
Médicaments et Technologies pour la Santé
( 531263 )
- CEA
- SPI
- Bât. 136 Saclay 91191 GIF-SUR-YVETTE
- France
9
San Raffaele Scientific Institute
( 225246 )
- Milan-I
- Italie
|
Langue du document |
Anglais
|
Nom de la revue |
|
Volume |
23
|
Numéro |
6
|
Page/Identifiant |
832-844.e6
|
Date de publication |
2018-06
|
Audience |
Internationale
|
Vulgarisation |
Non
|
Comité de lecture |
Oui
|
URL éditeur |
https://www.sciencedirect.com/science/article/pii/S1931312818302567?via%3Dihub
|
Domaine(s) |
|
DOI | 10.1016/j.chom.2018.05.002 |
PubMed Central | PMC6007033 |
Origine :
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